 Dr
Paul Gregorevic
Dr Paul Gregorevic is a muscle biologist, whose main interest is understanding the mechanisms of skeletal muscle adaptation, and their roles in serious illness. He is presently an Acting Assistant Professor at The University of Washington in Seattle, where he heads an independent research lab and the mouse physiology facility within the Paul D Wellstone Muscular Dystrophy Co-operative Research Centre – the first NIH funded center for cutting edge research into the causes and treatment of serious neuromuscular disorders. As of 2008, Dr Gregorevic will be relocating his research program in muscle biology and therapeutics development to the Baker Research Institute in Melbourne to combine his expertise with the advanced approaches being developed by eminent scientists in the Australian community.
Dr Gregorevic began his research career at The University of Melbourne in the laboratory of Dr David A. Williams, an authority on calcium imaging in contractile cells. There, he studied and established the sensitivity of muscle repair mechanisms to hyperoxic exposure, and for this research, was nominated to the Dean’s Honours List by the University’s School of Medicine. Dr Gregorevic subsequently undertook studies towards his PhD as an Australian Postgraduate Awardee in the laboratories of Dr Williams and later Dr Gordon S. Lynch, an internationally recognised expert on muscle mechanics and disease. In the course of his research on muscle regeneration and adaptation, Dr Gregorevic made key discoveries concerning the interplay of adrenergic agonists and growth-mediating cytokines upon the regulation of muscle hypertrophy. These and other important findings from his dissertation featured in numerous publications in distinguished journals and have since spawned a growing interest in cellular processes implicated in muscle growth.
Following the completion of his PhD, Dr Gregorevic pursued new avenues of research at The University of Melbourne concerning the therapeutic potential of growth factors for the treatment of serious neuromuscular conditions. His work identified significant potential to ameliorate the pathology of muscular dystrophies via manipulation of IGF-I related pathways, and has stimulated considerable research into the medical application of approaches related to these findings. In the course of Dr Gregorevic’s early post-doctoral work, he was invited to take up a research position at The University of Washington by Dr Jeffrey S. Chamberlain, the world’s foremost authority on gene therapy approaches for the treatment of Duchenne muscular dystrophy. Newly relocated to the United States, Dr Gregorevic set about developing and evaluating novel methods to achieve systemic in vivo gene transfer to striated musculature, using recombinant adeno-associated viral vectors. His work yielded the world’s first demonstration of body-wide gene delivery to the muscles of an adult mammal, which was published in Nature Medicine in 2004. His work was recognised with an invited presentation at the President’s Symposium at the American Society for Gene Therapy, and with an award for outstanding research at the American Society of Human Genetics that year.
A prestigious and internationally recognised Development Grant Award from the Muscular Dystrophy Association enabled Dr Gregorevic to pursue the adaptation of gene transfer technology for treatment of serious neuromuscular diseases. His progress on this front was recognised once again in Nature Medicine in 2006, where it was demonstrated for the first time ever that systemic administration of AAV vectors with a therapeutic transgene cassette could largely prevent the progression of muscular dystrophy in mice, and extend their prematurely shortened lifespan by up to four-fold. These critical findings provide compelling support for the concept of gene therapy as a legitimate prospect for treating the life threatening symptoms of muscle-related disease, and are the basis of forthcoming clinical trials in the USA. These and other achievements led to the Australian Physiological & Pharmacological Society to bestow upon Dr Gregorevic the 13 th A. K. McIntyre award in recognition of outstanding contributions to science. With an academic promotion at The University of Washington, Dr Gregorevic has since utilized vector-based gene transfer to pursue the processes controlling muscle adaptation in greater detail, and has established novel interventions that elicit acute and profound muscle hypertrophy with therapeutic potential in several models of muscle-related disease.
The development of in vivo gene delivery methods, and their use to unravel the mysteries of muscle related disease by Dr Gregorevic stands to revolutionize our approach to the treatment of not only heritable neuromuscular diseases, but many of the most prominent and serious medical conditions in our communities. As illnesses caused or complicated by striated muscle dysfunction are widely predicted to become the dominant contributor to premature death in the absence of new interventions, p revention and treatment of these conditions is vital to give many of our citizens back their lives, and to relieve growing burdens placed upon care providers, our healthcare system, and our economy. During the course of his Pfizer Australia Research Fellowship Dr Gregorevic will utilize his expertise with gene transfer and muscle biology to identify the key cellular processes that control striated muscle growth, and to elucidate their role in the development of specific disease states. By pursuing this research it is Dr Gregorevic’s hope that we might better understand those cellular events that place individuals at risk of serious illness, and more quickly identify future therapeutic strategies to combat illness in our population. The translation of this cutting edge science will also contribute to the advancement of Australia’s position as a supporter of innovative and internationally competitive research in globally important fields.
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 Dr Paul Thomas
Dr Paul Thomas is a Developmental Geneticist at the School of Molecular and Biomedical Science, University of Adelaide. The overall aim of Dr Thomas’s research is to understand the function of genes that cause neurodevelopmental disorders through the generation and analysis of knock-out and transgenic mouse models.
Dr Thomas’s interest in Developmental Biology began during his Ph.D. studies at the University of Adelaide, under the supervision of Prof. Peter Rathjen. Dr Thomas’s Ph.D. research focussed on the genetic control of murine Embryonic Stem (ES) cell differentiation. He identified several novel homeobox genes expressed by ES cells and showed that these genes were developmentally regulated during ES cell differentiation. In 1995, Dr Thomas moved in London to take up a post-doctoral research position in the laboratory of the internationally renowned embryologist Dr Rosa Beddington at the National Institute for Medical Research. Dr Thomas continued his research into the genetic control of early mammalian development, focusing on the mechanism by which the anterior-posterior axis is established. Dr Thomas identified a novel signaling centre, the anterior visceral endoderm (AVE), which is essential for the specification of anterior identity and forebrain development. Dr Thomas also showed that two of the homeobox genes that he originally identified in ES cells, Hesx1 and Hex, are expressed in the AVE are key determinants of anterior identity. Dr Thomas also isolated the human HESX1 gene and was part of a team which showed that mutations in this gene cause the severe congenital neurodevelopmental syndrome Septo-optic Dysplasia. These seminal discoveries were published in leading international journals including Nature Genetics, Current Biology and Development.
In recognition of his post-doctoral achievements, Dr Thomas was awarded a Howard Florey Centenary Research Fellowship from the Australian National Health & Medical Research Council (NHMRC), and returned to Australia in 1998 as research fellow at the Murdoch Institute (now the Murdoch Childrens Research Institute) in Melbourne. Over the next eight years, Dr Thomas established an independent and productive research program, supported primarily by competitive grant funding from the NHMRC. His investigations into the developmental genetics of forebrain and hypothalamic-pituitary axis development and adult pituitary stem cells have been published in several prominent Developmental Biology, Genetics and Endocrine journals.
In 2006, Dr Thomas relocated to the University of Adelaide as a self-funded senior research fellow. Dr Thomas continues to investigate the developmental and genetic basis of mammalian neurogenesis through the generation of mouse models for X-linked Mental Retardation (MR) syndromes. Most recently, Dr Thomas has pioneered research into the genetic basis of X-linked Hypopituitarism, and shown that this MR syndrome is caused by altered dosage of the CNS transcription factor SOX3. His group has generated clinically-relevant mouse models that are beginning to provide detailed understanding of the mechanism of vertebrate neurogenesis and the molecular pathology of XH. The Pfizer Australia Research Fellowship awarded to Dr Thomas provides critical support for this important area of research, and in the longer term will allow Dr Thomas to expand his research program to include novel X-linked MR genes. Ultimately, these studies will generate a detailed portrait of the developmental and molecular mechanisms that lead to impaired neurodevelopment in mice and man and provide a unique resource for the development of novel therapeutic options for patients with MR.
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